Fast dissolving vaginal film formulations of topical microbicides may provide more efficient vaginal drug delivery than gels because films dissolve directly into vaginal fluid. In this first in human Phase 1 study of tenofovir vaginal films, the safety, PK, and PD of gel and two doses of film formulations of tenofovir were compared to matched placebo.
75 healthy HIV negative women (mean age 27.9, 73% white) were randomized to 1 of 5 arms: 1) 4 mL of daily tenofovir 1% gel containing 40mg of tenofovir, 2) 4 mL of placebo gel, 3) 10 mg tenofovir film, 4) 40 mg tenofovir film or 5) placebo film used daily for 7 days. All films were 2 X 2 inches. Adverse event (AE) data were collected via questionnaire and physical exam at follow-up visits on day 7 and 30. Grade 2 and higher AEs deemed related to study product were compared across arms using Fisher’s exact test. Plasma tenofovir was measured before and 2 hours after the last product use. Two hours after final product use, two sets of cervical biopsies were obtained, of which one set was assessed for tissue tenofovir-diphosphate levels and the other exposed to HIV-1 in an ex-vivo challenge assay. Tissue HIV infection was monitored by p24 levels in culture supernatant.
There was 1 Grade 2 related AE for vaginal pain in the tenofovir gel group and no difference in the rate of urogenital complaints between groups. After 6 daily doses, women in the 40 mg film group had 4-fold higher concentrations of tenofovir in plasma compared to either the 10 mg film or 40 mg gel group (1.9, 0.4, and 0.5 ng/mL respectively), suggesting that women using the 40 mg film had higher plasma trough levels. Two hours after the 7th dose, median concentrations in plasma were comparable in the 40 mg film and gel groups (2.6 and 2.3 ng/mL) while the 10 mg film group was lower (1.0 ng/mL). Cervical tissue biopsies obtained from women after 7 days of tenofovir film or gel use had significantly lower HIV infectivity than placebo treated women. As shown in Figure 1, there was a significant PK/PD correlation in cervical tissue with higher tenofovir-diphosphate concentrations correlated with lower HIV replication (Figure 1).
This study demonstrates that vaginal films can efficiently and safely deliver tenofovir to the cervicovaginal tissues, achieving plasma levels higher than those of gels containing identical doses of drug. All active products were protective against HIV-1 infection in the ex-vivo challenge model using cervical tissue.